Combinatorial library synthesis and pharmaceutically active compounds produced thereby

ABSTRACT

The invention provides new methods for synthesis of nucleotide-based compounds and new libraries of such compounds. Compounds of the invention are useful for a variety of therapeutic applications, including treatment of viral or bacterial infections and associated diseases and disorders.

[0001] This application claims the benefit of U.S. ProvisionalApplication Serial No. 60/164,036 filed Nov. 8, 1999, and U.S.Provisional Application Serial No. 60/172,508 filed Dec. 17, 1999, theteachings of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The invention provides new methods for synthesis ofnucleotide-based compounds and libraries of such compounds. Compounds ofthe invention are useful for a variety of therapeutic applications,including treatment of viral or bacterial infections and associateddiseases and disorders.

[0004] 2. Background

[0005] The important initial step in the development of therapeuticagents is the discovery of compounds that bind to a protein, enzyme orreceptor of interest. Through careful structure/activity work ofresulting active compounds, one arrives at a lead compound for furtherdevelopment into a clinical candidate. This traditional process of drugdiscovery is a long and arduous endeavor. Often it takes 10 to 15 yearsbefore a new drug makes it into the marketplace.

[0006] Recent advances in molecular biology and genomics have led toidentification of new molecular targets for drug discovery. As a resultof the limitation of traditional drug discovery, new approaches to thediscovery of therapeutics have been developed. In the more modernapproaches, large libraries of diverse compounds are synthesized by anumber of methods and subjected to high throughput in vitro screeningagainst a particular molecular target implicated in a disease. Theactive compounds so identified are then subjected to Structure-ActivityRelationship (SAR) work to eventually identify the lead compound.

[0007] Modern drug discovery approaches entail the synthesis andscreening of libraries of compounds. The design and synthesis of suchlibraries is often based on a unique molecular skeleton or scaffold. Byincorporating a variety of structural elements into a scaffold, local aswell as global molecular diversity can be achieved which facilitatesspecific interactions between a ligand and its receptor. The structuralelements contribute to molecular diversity by variable spatial displayof ionic, hydrogen-bonding, charge-transfer and van der Waalsinteractions thus allowing for the selection of the best ‘fit’ betweenthe ligand and its receptor.

[0008] Traditionally, libraries have been constructed usingsolid-support synthesis methods, such as synthesis of a library on‘beads’. Solid support methods are useful because reactive products canbe readily isolated in a relatively pure form by simply washing awayexcess reagents and solvents from the support matrix, something that isnot possible with solution based methods.

[0009] One method for generating compound libraries utilizes a discretecompound approach. In the discrete compound approach, compounds aresynthesized in parallel each in a separate reaction vessel. The identityof each compound is known or can be ascertained by analytical methods.Various methods for constructing discrete compound libraries are knownin the art. For example, the Pin method (H. M. Geyson et al., PNAS, USA81: 3998-4002 (1984)) utilizes polyethylene pins placed in a 96-wellsupporting block. Each pin is coated with polymeric material that isderivatized for anchoring functional groups. The reactions can be run on100 nmol to 50 micromol scale and the products subjected to multiplebiological assays. The Diversomer apparatus approach (S. H. Dewitt etal., PNAS, USA 90: 6909-6913 (1993)) utilizes a series of porous gasdispersion tubes which serve as containers for resin beads and reagentsand solvents are placed in vials mounted on a reservoir block. The endsof the gas dispersion tubes are placed in the vials and the reagents areallowed to diffuse through the porous membrane and contact the resinsupport. The apparatus can be placed in a manifold with an injectablegasket. The porous frit apparatus utilizes each well of a deep wellmicrotiter plate fitted with porous frits. The plate is clamped on to aviton gasket. In between synthetic steps in a sequence, the reactionsolution can be drained and the resin rinsed by removal of the vitongasket. The spatially addressable, light directed parallel synthesismethod utilizes a photolithographic method to synthesize 100,000separate compounds. The synthesis is done on a silicon wafer (chip) thatis functionalized to attach to a leader molecule which carries aphotolabile protecting group at its reaction site. Once unmasked byillumination, the reactive group is unmasked which can then enter into aspecific chemical reaction with a reactant. The library of compoundsremain tethered to the solid support. The structure of the compound ineach specific location is known.

[0010] Another method for generating compound libraries utilizes a mixand pool synthesis approach. This approach allows large libraries ofcompounds to be synthesized by pooling different sets of support-boundintermediates. However, this method only works when all of the reactantsin a mixture have similar reactivities. Reaction conditions need to beoptimized before attempting a split and pool strategy. This strategy hasbeen used to synthesize libraries of peptides and oligonucleotides.Various mix and pool synthesis approaches are known in the art. Forexample, Houghten et al. (C. Pinilla et al., Biopolymers, Pept. Sci.,37: 221-240 (1995), pioneered this approach by preparing pools ofcompounds that each contain structurally defined building blocks at oneor two positions. Once the pool with the highest activity is identifiedin an in vitro assay, the deconvolution process begins. Iterative roundsof synthesis and biological assays are carried out until a molecule withthe highest activity is identified. Modifications of this approachinclude the positional scanning approach developed by Houghten et al.(C. Pinilla et al., Biopolymers, Pept. Sci., 37: 221-240 (1995) and theorthogonal approach developed by Tartar et al. (B. Deprez, et al., J.Am. Chem. Soc., 117: 5405-5406 (1995). Another mix and pool synthesisapproach utilizes beads encoded by oligonucleotides of known sequence totrace compounds.

[0011] Biological assays used to test the activity of compound librariescan be carried out with the compounds immobilized on a solid support orin solution. For example, a resin-bound library can be treated with afluorescent-labeled receptor and the compound-bound receptors isolatedusing a fluorescence activated cell sorting instrument. Structuredetermination can be done, for example, by sequencing or massspectrometry analysis. When assays are performed in solution, thecompounds need to be released from the solid support. A portion of thebeads are released and contacted with the receptor. The active compoundsare then traced back to the original bead. Structure determination canbe performed by analytical methods.

[0012] See also: C. Pinilla et al., Biopolymers, Pept. Sci 37: 221-240(1995); S. H. DeWitt et al., PNAS, USA 90: 6909-6913 (1993); B. Deprezet al., J. Am. Chem. Soc. 117: 5405-5406 (1995); H. M. Geyson, et al.PNAS, USA 81: 3998-4002 (1984); G. Jung et al., Angew. Chem. Intl. Ed.Engl. 31: 367-383 (1992); M. R. Pavia, et al. Bioorg. Med. Chem. Lett.3: 387-396 (1993); E. M. Gordon et al., J. Med. Chem. 37: 1385-1401(1994); L. A. Thompson et al., Chem. Rev. 96: 555-600 (1996); S. Vermaet al., Annu. Rev. Biochem. 67: 99-134 (1998); S. L. Beaueage et al.,Tetrahedron Lett. 22: 1859-1862 (1981); R. P. Iyer et al., InComprehensive Natural Products, D. H. R. Barton and K. Nakanishi Eds.,Elsevier Science. Vol 7 (In press); A. D. Barone et al., Nucl. AcidsRes. 12: 4051-4061 (1984); R. P. Iyer et al., J. Am. Chem. Soc. 112:1253-54 (1990).

SUMMARY OF THE INVENTION

[0013] We have now found new nucleotide-based compounds that are usefulfor a variety of therapeutic applications, including to treat againstviral or bacterial infections.

[0014] The invention also provides new methods for synthesis ofnucleotide-based compounds and new libraries of such compounds. Inparticular, the invention provides new methods for construction ofcompound libraries utilizing a nucleic acid-based (NAB) scaffold. Thisapproach enables incorporating structural elements that can provide both“sequence-specific” interactions (e.g., hydrogen-bonding interactionsbetween nucleobases) as well as “shape-specific” motifs (e.g., bulgesand stem-loop structures) that can allow specific recognition of othernucleic acids and proteins. Libraries based on NAB scaffold canpotentially mimic the molecular recognition that exists between cellularmacromolecules and biomolecules such as hormones, nucleotides and theirreceptors.

[0015] The invention provides methods for constructing compoundlibraries by solution-phase or solid-phase approaches. Preferred librarysyntheses of the invention are carried out on a solid support. Suitablesolid supports include, for example, pins, beads, resins, chips, etc.

[0016] Preferred library syntheses of the invention include use ofcolumns capable of agitation (e.g. spin or other rotation) and that maysuitably contain a resin support material. Reactants are placed in thecolumn, and the column preferably shaken or otherwise agitated duringreaction. Additional reactants can be added to provide repeated reactioncycles. Reagents and reaction products also can be convenientlyseparated and removed from the column, e.g. by centrifuging a reactioncolumn to facilitate removal (e.g. by filtration) of desired material.

[0017] Other aspects of the invention are disclosed infra.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018]FIG. 1 provides a flow diagram for library assembly.

DETAILED DESCRITPTION OF THE INVENTION

[0019] As discussed above, we have discovered new methods forconstruction of a compound library. Preferred library members includecompounds of the following Formula I or I′:

[0020] wherein L is a linking group such as e.g. an amide, ester,diester or the like, or an optionally substituted alkylene (e.g. C₁₋₂₀alkylene), optionally substituted alkenylene (e.g., C₂₋₂₀ alkenylene) oralkynylene (e.g., C₂₋₂₀ alkynylene) having such groups either as a chainmember of pendant to the chain, and which may be optionally substitutedwith one or more substituents selected from a group consisting of O, S,Se, NR¹NR², CR¹CR², OR, SR and SeR (R, R¹ and R² defined below), or anenzymatically reactive (particularly, cleavable) moiety such as anamide, ester, and the like;

[0021] Q is carbon or a heteroatom such as O, S or N;

[0022] R is hydrogen or a hydroxyl group or a hydrophobic group, e.g. amoiety having from 1 to about 18 carbon atoms, such as optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aralkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkenyl, optionallysubstituted carbocyclic aryl, an optionally substituted mononucleotide,an optionally substituted polynucleotide, or an optionally substitutedheteroaromatic or heteroalicyclic group preferably having from 1 to 3separate or fused ring and 1 to 3 N, O or S atoms;

[0023] R¹, R², R³ and R⁴ are each independently selected from a group asdefined by R;

[0024] B is optionally substituted adenine, optionally substitutedthymidine, optionally substituted cytosine or an optionally substitutedguanine, preferably where the optional substituents are alkyl,carbocyclic aryl, or heteroaromatic or heteroalicyclic group preferablyhaving from 1 to 3 separate or fused rings and 1 to 3 N, O or S atoms,or B is heteroaromatic or heteroalicyclic group other than an adenine,thymidine, cytosine or guanine and preferably has from 1 to 3 separateor fused rings and 1 to 3 N, O or S atoms;

[0025] n is an integer of from 1 to 5 and where n is greater than 1designates that corresponding additional carbon ring or acyclic membersare present (i.e. where n is 2 an additional carbon ring member (to forma 6-membered ring) or acyclic carbon is present; where n is 3, twoadditional carbon ring members (to form a 7-membered ring) or acycliccarbon is present, and so on);

[0026] and pharmaceutically acceptable salts thereof.

[0027] In the above Formulae I and I′, it is understood that the dashedline indicates the ring may be in the open or closed configuration.

[0028] The depicted sugar group may be natural or modified (e.g.synthetic) form, or in an open chain form (where one of the depictedring bonds would not be present).

[0029] Preferred R groups of compounds of formulae I and I′ includecyclic groups, particularly alicyclic groups that may comprise one ormore single or polycyclic rings, particularly a bridged or fused ringstructure, with 0, 1 or 2 endocyclic carbon-carbon double bonds.Additional preferred R groups include heteroalicyclic moieties,particularly heteroalicyclic groups having from 5 to about 8 ringmember, preferably with one or two O, N or S ring members, particularlyone or two oxygen ring members.

[0030] Preferred compounds of the invention include those of formulae Iand I′ where the nucleoside is linked to the R group via a phosphorousgroup at the 5′ end. Other dephospholinkers such as carbonates,carbamates, ureas, acetals, etc., may also be used. Such linkages couldalso be established via the 2′ or 3′ sites of the nucleoside. When R isa nucleoside, linkages can be via 5′ to 3′, 5′ to 5′, 3′ to 3′, 2′ to 5′and 2′ to 2′, or any combination thereof, of the participatingnucleosides.

[0031] Preferred library members include compounds of the followingFormula II or II′:

[0032] wherein X and Y are each independently selected from a groupconsisting of O, S, Se, NR¹NR², CR¹CR², OR, SR and SeR, or one or bothof X and Y are an enzymatically reactive (particularly, cleavable)moiety such as an amide, ester, and the like;

[0033] R is a hydrophobic group, e.g. a moiety having from 1 to about 18carbon atoms, such as optionally substituted alky, optionallysubstituted alkenyl, optionally substituted alknyl, optionallysubstituted aralkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkenyl, optionally substituted carbocyclic aryl, anoptionally substituted mononucleotide, an optionally substitutedpolynucleotide, or an optionally substituted heteroaromatic orheteroalicyclic group preferably having from 1 to 3 separate or fusedring and 1 to 3 N, O or S atoms;

[0034] R¹, R² and R³ are each independently selected from a group asdefined by R;

[0035] B is optionally substituted adenine, optionally substitutedthymidine, optionally substituted cytosine or an optionally substitutedguanine, preferably where the optional substituents are alkyl,carbocyclic aryl, alknyl, or heteroaromatic or heteroalicyclic grouppreferably having from 1 to 3 separate or fused rings and 1 to 3 N, O orS atoms, or any heterocyclic structure that is covalently linked to thesugar ring;

[0036] and pharmaceutically acceptable salts thereof.

[0037] In the above Formulae II and II′, it is understood that thedashed line extending to each of the substituents X and Y designatesthat one, but not both, of X and Y may have an additional chemical bond(i.e. a double bond).

[0038] The depicted sugar group may be natural or modified (e.g.synthetic) form, or in an open chain form (where one of the depictedring bonds would not be present).

[0039] Preferred R groups of compounds of formulae II and II′ includecyclic groups, particularly alicyclic groups that may comprise one ormore single or polycyclic rings, particularly a bridged or fused ringstructure, with 0, 1 or 2 endocyclic carbon-carbon double bonds.Additional preferred R groups include heteroalicyclic moieties,particularly heteroalicyclic groups having from 5 to about 8 ringmember, preferably with one or two O, N or S ring members, particularlyone or two oxygen ring members.

[0040] As mentioned above, either one or both of X and Y may be anenzymatically reactive group, i.e. the group may be cleavable orotherwise reactive in vivo upon administration to a mammal, particularlya human. Preferred enzymatically reactive groups include e.g. amides(which may be cleaved in vivo with an amidase), esters (which may becleaved in vivo with an esterase), and acetal and ketal groups.

[0041] Preferred compounds of the invention include those of formulae IIand II′ where the nucleoside is linked to the R group via a phosphorousgroup at the 5′ end. Other dephospholinkers such as carbonates,carbamates, ureas, acetals, etc., may also be used. Such linkages couldalso be established via the 2′ or 3′ sites of the nucleoside. When R isa nucleoside, linkages can be via 5′ to 3′, 5′ to 5′, 3′ to 3′, 2′ to 5′and 2′ to 2′, or any combination thereof, of the participatingnucleosides.

[0042] Preferably, compounds of the invention will be present inenantiomerically enriched mixtures, i.e. where one enantiomer is presentin a greater amount than other stereoisomer(s) of the compound,particularly where one enantiomer is present in amount of at least about60 mole percent, relative to all stereoisomers present of the compound;preferably where one enantiomer is present in amount of at least about70 or 80 mole percent, relative to all stereoisomers present of thecompound; still more preferably where one enantiomer is present inamount of at least about 85, 90, 92, 95, 96, 97, 98 or 99 mole percent,relative to all stereoisomers present of the compound

[0043] Preferred compounds of the invention include those of thefollowing Formulae IIA and IIA′, having the depicted configurations:

[0044] X, Y, R, R¹, R², B, R³ and n are the same as defined above forFormulas II and II′; and pharmaceutically acceptable salts thereof.

[0045] In the above Formulae IIA and IIA′, it is understood that thedashed line extending to each of the substituents X and Y designatesthat one, but not both, of X and Y may have an additional chemical bond(i.e. a double bond).

[0046] In the above Formulae IIA and IIA′, the depicted sugar group maybe natural or modified (e.g. synthetic) form, or in an open chain form(where one of the depicted ring bonds would not be present).

[0047] In the above Formulae I, I′, II, II′, IIA and IIA′, alkyl groupspreferably contain from 1 to about 18 carbon atoms, more preferably from1 to about 12 carbon atoms and most preferably from 1 to about 6 carbonatoms. Specific examples of alkyl groups include, for example, methyl,ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl etc.

[0048] In the above Formulae I, I′, II, II′, IIA and IIA′, aralkylgroups include the above-listed alkyl groups substituted by acarbocyclic aryl group having 6 or more carbons, for example, phenyl,naphthyl, phenanthryl, anthracyl, etc.

[0049] In the above Formulae I, I′, II, II′, IIA and IIA′, cycloalkylgroups preferably have from 3 to about 8 ring carbon atoms, e.g.cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,1,4-methylenecyclohexane, adamantyl, cyclopentylmethyl,cyclohexylmethyl, 1- or 2-cyclohexylethyl and 1-, 2- or3-cyclohexylpropyl, etc.

[0050] In the above Formulae I, I′, II, II′, IIA and IIA′, exemplaryheteroaromatic and heteroalicyclic group include pyridyl, pyrazinyl,pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl,indolyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl,piperidinyl, morpholino and pyrrolidinyl.

[0051] Mononucleotides of compounds of the invention (compounds ofFormulae I, I′, II, II′, IIA and IIA′) invention include adenine,cytosine, guanosine and thymidine.

[0052] Polynucleotides of compounds of the invention (compounds ofFormulae I, I′, II, II′, IIA and IIA′) preferably contain from about 1to about 20 mononuculeotides, more preferably from 1 to about 10mononuculeotides and still more preferably from 1 to about 5mononuculeotides. The polynucleotides are suitably constructed such thatthe 5′ group of one mononucleotide pentose ring is attached to the 3′group of its neighbor in one direction via, for example, aphosphodiester or a phosphorthioate internucleotide linkage.

[0053] Sugar groups of compounds of the invention may be comprised ofmono-, di-, oligo- or poly-saccharides wherein each monosaccharide unitcomprises from 3 to about 8 carbons, preferably from 3 to about 6carbons, containing polyhydroxy groups or polyhydroxy and amino groups.Non-limiting examples include glycerol, ribose, fructose, glucose,glucosamine, mannose, galactose, maltose, cellobiose, sucrose, starch,amylose, amylopectin, glycogen and cellulose. The hydroxyl and aminogroups are present as free or protected groups containing e.g. hydrogensand/or halogens. Preferred protecting groups include acetonide, t-butoxycarbonyl groups, etc. Monosaccharide sugar groups may be of the L or Dconfiguration and a cyclic monosaccharide unit may contain a 5 or 6membered ring of the α or β conformation. Disaccharides may be comprisedof two identical or two dissimilar monosaccharide units.Oligosaccharides may be comprised of from 2 to 10 monosaccharides andmay be homopolymers, heteropolymers or cyclic polysugars.Polysaccharides may be homoglycans or heteroglycans and may be branchedor unbranched polymeric chains. The di-, oligo- and poly-saccharides maybe comprised of 1→4, 1→6 or a mixture of 1→4 and 1→6 linkages. The sugarmoiety may be attached to the link group through any of the hydroxyl oramino groups of the carbohydrate.

[0054] Preferred compounds of the invention comprise R groups containingone of the hydrophobic structures represented in Table 1 below.

[0055] Preferred library syntheses of the invention are carried out on asolid support. Suitable solid supports include, for example, pins,beads, resins, chips, etc. Particularly preferred methods are thosecarried out using beads as the solid support.

[0056] Phospholinked compounds of the invention can be prepared asgenerally depicted in Scheme I. In addition to the synthetic routedepicted in Scheme 1, library compounds may also be assembled using aphosphodiester approach, a phosphortriester approach and/or theH-phosphonate methodology (R. P. Iyer et al. In Comprehensive NaturalProducts, D. H. R. Barton and K. Nakanishi Eds., Elsevier Science Vol 7,in press). In Scheme I below, preferred stereoisomers and substituentgroups are depicted, although it is understood that other compounds ofthe invention can be produced by the same or similar procedures.

[0057] Scheme I shows the preparation of library compounds usingphosphoramidite chemistry (S. L. Beaueage et al., Tetrahedron Lett. 22:1859-1862 (1981); R. P. Iyer et al., In Comprehensive Natural Products,D. H. R. Barton and K. Nakanishi Eds. Elsevier Science. Vol. 7 (inpress)). A key synthon is the solid-support-bound phosphoramidite, shownas compound 2 of Scheme I. Compound 2 can be prepared by5′-phosphitylation of controlled-pore-glass (CPG)-bound nucleoside,shown as compound 3 of Scheme I. β-cyanoethylbis(N,N-diisopropylamino)phosphine (CNP) in the presence ofN,N-diisopropylammonium tetrazolide was used as the phosphitylatingreagent, which produced byproducts soluble in methylene chloride. Thereaction mixture was filtered and a quantitative yield of compound 2 wasobtained. Each CPG-bound nucleoside phosphoramidite (compound 2) couldbe stored in vacuo for subsequent use in library synthesis.

[0058] The library synthesis was performed in a parallel format usingQIAquick® spin columns (Quiagen) each of which was equipped with asepharose resin supported by a nitrocellulose filter at the bottom (FIG.1). The reactants were placed in the spin columns and the contentsshaken were shaken during the reaction. The columns were then placed ina recepticle vial and centrifuged allowing facile filtration of themixture into the recepticle. The next reactant was then added to thespin columns and the process repeated until the library synthesis wascomplete.

[0059] Typically for the synthesis of the library (Scheme I, FIG. 1), ameasured amount of CPG-bound phosphoramidite (compound 2) wastransferred to a series of spin columns. The alcohols 4a-f were added tothe spin columns along with tetrazole in acetonitrile and incubated for5 minutes. The spin columns were then centrifuged to separate out theunreacted materials and byproducts from the support-bound coupledproduct 5a-x as a mixture of Rp and Sp diastereomers. The oxidativesulfurization of 5a-x was performed using either3H-1,2-berizodithiole-3-one-1,1-dioxide (0.1 M in acetonitrile) or I₂solution (0.02 M in Pyridine/H₂O/tetrahyrofuran) to produce the supportbound phosphotriesters 6a-x or 7a-x, respectively. The support-boundlibrary was heated with NH₄OH (28%, 55° C., 5 hours) to remove the crudediesters. Each of the crude products were passed through a Sep-Pakcartridge® (Waters) to give products 1a-x. It is to be noted thatoxidative sulfurization and oxidation can also be carried out usingother sulfurizing and oxidizing agents.

[0060] Table 1 below shows the members of a representative 24-memberlibrary. The library members were analyzed using reversed-phase HPLC anddetermined to be 90-95% pure. TABLE 1 Representative Library members(1a-x), and their HPLC retention time (R_(t) min).

B Pdt R_(t) Pdt R_(t) Pdt R_(t) Pdt R_(t) Pdt R_(t) Pdt R_(t) A 1a 30.51e 34.3 1i 47.8 1m 45.0 1q 36.0 1u 43.3 C 1b 28.6 1f 33.3 1j 47.5 1n44.1 1r 35.1 1v 42.7 G 1c 28.1 1g 31.7 1k 46.5 1o 42.9 1s 33.6 1w 41.0 T1d 29.7 1h 37.8 1l 48.2 1p 47.4 1t 38.2 1x 46.5

[0061] When prepared as a mixture, compound libraries of the inventionpreferably will contain at least about 2, 3, 4 or 5 distinct compounds,more preferably at least about 10 distinct compounds, still morepreferably at least about 20, 30, 40, 50 ,60, 70, 80, 90 or 100compounds, and may contain 200, 300, 400 or 500 or more compounds.

[0062] Table 2 shows examples of additional representative hydrophobicgroups which may be linked to the 5′ end of ribo- anddeoxyribonucleosides via linkages. Specific examples of hydrophobicgroups include saturated and unsaturated acyclic and cyclic alcohols,aromatic and heterocyclic alcohols. Exemplary groups demonstrated intable 2 include primary and secondary alcohols. However, one of skill inthe art will recognize that the methods may be extended to other kindsof structural variants, specifically those hydrophobic groups bearingmultiple functionalities, such as for example, ether, keto, amino, haloin addition to the hydroxy groups. Further, one of skill in the artwould also recognize that the methods disclosed may be useful forlinkage to additional available sites such as the 3′ and 2′ sites. TABLE2 open-chain cyclic primary cyclic secondary aromatic alcohol alcoholalcohol alcohol

[0063] Compounds of the invention (compounds of Formulae I, I′, II, II′,IIA and IIA′) will be useful for a variety or therapeutic applications,such as bacterial or viral infections. For example, methods of theinvention include treatment against infections and diseases associatedwith viruses, which methods in general comprise administration of atherapeutically effective amount of one or more compounds of Formulae I,I′, II, II′, IIA or IIA′ to virally infected cells, such as mammaliancells, particularly human cells.

[0064] More specifically, the invention includes methods of treatment ofa mammal susceptible to (prophylactic treatment) or suffering from adisease associated with DNA and RNA viruses; examples include viruses ofthe herpes family, e.g. herpes simplex viruses (HSV) including herpessimplex 1 and 2 viruses (HSV 1, HSV 2), varicella zoster virus (VZV;shingles), human herpes virus 6, cytomegalovirus (CMV), Epstein-Barrvirus (EBV), and other herpes virus infections such as feline herpesinfections, and diseases associated with hepatitis viruses includinghepatitis B (HBV) and C (HCV) viruses. Examples of clinical conditionswhich are caused by such viruses include herpetic keratitis, herpeticencephalitis, cold sores and genital infections (caused by herpessimplex), chicken pox and shingles (caused by varicella zoster) andCMV-pneumonia and retinitis, particularly in immunocompromised patientsincluding renal and bone marrow transplant and patients with AcquiredImmune Deficiency Syndrome (AIDS). Epstein-Barr virus can causeinfectious mononucleosis, and is also suggested as the causative agentof nasopharyngeal, immunoblastic lymphoma and Burkitt's lymphoma.

[0065] Compounds of the invention also will be useful for cancertherapy, particularly to treat solid tumors, such as may be present inthe liver, lung, brain or other tissue.

[0066] Compounds of the invention also will be useful for treatmentagainst bacterial infections, including both Gram positive and Gramnegative bacteria, and mycobacteria.

[0067] Administration of compounds of the invention may be made by avariety of suitable routes including oral, topical (includingtransdermal, buccal or sublingal), nasal and parenteral (includingintraperitoneal, subcutaneous, intravenous, intradermal or intramuscularinjection) with oral or parenteral being generally preferred. It alsowill be appreciated that the preferred method of administration anddosage amount may vary with, for example, the condition and age of therecipient.

[0068] Compounds of the invention may be used in therapy in conjunctionwith other pharmaceutically active medicaments, such as anotheranti-viral agent, or an anti-cancer agent. Additionally, while one ormore compounds of the invention may be administered alone, they also maybe present as part of a pharmaceutical composition in mixture withconventional excipient, i.e., pharmaceutically acceptable organic orinorganic carrier substances suitable for parenteral, oral or otherdesired administration and which do not deleteriously react with theactive compounds and are not deleterious to the recipient thereof.Suitable pharmaceutically acceptable carriers include but are notlimited to water, salt solutions, alcohol, vegetable oils, polyethyleneglycols, gelatin, lactose, amylose, magnesium stearate, talc, silicicacid, viscous paraffin, perfume oil, fatty acid monoglycerides anddiglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose,polyvinylpyrrolidone, etc. The pharmaceutical preparations can besterilized and if desired mixed with auxiliary agents, e.g., lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure, buffers, colorings, flavorings and/oraromatic substances and the like which do not deleteriously react withthe active compounds.

[0069] For parenteral application, particularly suitable are solutions,preferably oily or aqueous solutions as well as suspensions, emulsions,or implants, including suppositories. Ampules are convenient unitdosages.

[0070] For enteral application, particularly suitable are tablets,dragees or capsules having talc and/or carbohydrate carrier binder orthe like, the carrier preferably being lactose and/or corn starch and/orpotato starch. A syrup, elixir or the like can be used wherein asweetened vehicle is employed. Sustained release compositions can beformulated including those wherein the active component is protectedwith differentially degradable coatings, e.g., by microencapsulation,multiple coatings, etc.

[0071] Therapeutic compounds of the invention also may be incorporatedinto liposomes. The incorporation can be carried out according to knownliposome preparation procedures, e.g. sonication and extrusion. Suitableconventional methods of liposome preparation are also disclosed in e.g.A. D. Bangham et al., J. Mol. Biol., 23:238-252 (1965); F. Olson et al.,Biochim. Biophys. Acta, 557:9-23(1979); F. Szoka et al., Proc. Nat.Acad. Sci., 75:4194-4198 (1978); S. Kim et al., Biochim. Biophys. Acta,728:339-348 (1983); and Mayer et al., Biochim. Biophys. Acta,858:161-168 (1986).

[0072] It will be appreciated that the actual preferred amounts ofactive compounds used in a given therapy will vary according to thespecific compound being utilized, the particular compositionsformulated, the mode of application, the particular site ofadministration, etc. Optimal administration rates for a given protocolof administration can be readily ascertained by those skilled in the artusing conventional dosage determination tests.

[0073] All documents mentioned herein are incorporated herein byreference.

[0074] The present invention is further illustrated by the followingexamples. These examples are provided to aid in the understanding of theinvention and are not to be construed as limitations thereof.

EXAMPLE 1

[0075] Preparation of the CPG-bound Phosphoramidite (Compound 2) 2a-d.

[0076] Each of the CPG-bound nucleosides 3a-d (3 g, 0.228 mmol), alongwith bis-(N,N-diisopropylamino)-2-cyanoethylphosphine (0.36 mL, 1.14mmol), bisdiisopropylammonium tetrazolide (850 mg) in methylene chloride(50 mL) were placed in flasks and shaken at 30° C. overnight. TheCPG-bound phosphoramidite 2a-d was collected by filtration and washedsequentially with CH₂Cl₂ (200 mL), CH₃CN (100 mL) and anhydrous ether(50 mL) and dried in vacuo.

EXAMPLE 2

[0077] Synthesis of a 24 Member Library 1-6, a-d (Products 1a-x) (SeeScheme 1, Table 1).

[0078] Step 1: The CPG-bound phosphoramidites 2a-d (5 mmol) were placedin spin columns. A solution of tetrazole (0.5 mL, 0.45 M in CH₃CN) wasadded. The appropriate alcohols 4a-f (25 mmol) were added to thereaction mixture. The mixture was shaken for five minutes and thesolvent removed by centrifugation and decanted. The CPG was then washedwith CH₃CN (2×0.5 mL).

[0079] Step 2: The CPG was then soaked in a solution of3H-1,2-benzodithiole-3-one-1,1-dioxide in CH₃CN (0.1 M, 0.5 mL). Themixture was shaken at room temperature for five minutes. The solvent wasremoved and the CPG washed with acetonitrile (2×0.5 mL) and dried underargon.

[0080] Step 3: The CPG was transferred to a conical screwcap tube (1.5mL, VWR) and ammonium hydroxide (28%, 1.5 mL) added. The mixture washeated at 55° C. for 4 hours. The suspension was cooled and centrifuged.The supernatant containing the desired products were collected in aspeed vac to give 1-6, a-d (products 1a-x).

[0081] Typical spectral data are as follows:

[0082] Nucleoside 1a: ¹H NMR (D₂O): δ 8.44 (d, 1H, J=9.2 Hz), 8.21 (s,1H), 6.44-6.47 (m, 1H), 4.24 (s, 1H), 3.96-4.06 (m, 2H), 3.55-3.64 (m,2H), 2.81-2.88 (m, 1H), 2.57-2.62 (m, 1H), 1.30-1.35 (m, 2H), 1.04-1.09(m, 2H), 0.67 (t, 3H, J₁=7.5 Hz, J₂=7.3 Hz) ppm; ³¹P NMR (D₂O): δ 58.97,58.64 ppm; MS (negative mode): calcd. for C₁₄H₂₁N₅O₅PS, 402 (M); foundm/z, 402.

[0083] Nucleoside 1b: ¹H NMR (D₂O): δ 8.05 (d, 1H, J=7.7 Hz), 6.24 (t,1H, J=6.6 Hz), 6.10 (d, 1H, J=7.8 Hz), 4.50-4.53 (m, 1H), 4.19 (s, 1H),4.03-4.12 (m, 2H), 3.84-3.88 (m, 2H), 2.40-2.45 (m, 1H), 2.24-2.29 (m,1H), 1.51-1.57 (m, 2H), 1.25-1.33 (m, 2H), 0.83 (t, 3H, J₁=7.5 Hz) ppm;³¹P NMR (D₂O):δ 58.96 ppm; MS (negative mode): calcd. for C₁₃H₂₁N₃O₆PS,378 (M); found m/z, 378.

[0084] Nucleoside 1c: ¹H NMR (D₂O): δ 8.04 (d, 1H, J=5.4 Hz), 6.24-6.28(m, 1H), 4.19 (s, 1H), 3.96-4.05 (m, 2H), 3.63-3.68 (m, 2H), 2.78-2.85(m, 1H), 2.47-2.52 (m, 1H), 1.34-1.41 (m, 2H), 1.07-1.13 (m, 2H), 0.71(t, 3H, J₁=7.5 Hz) ppm; ³¹P NMR (D₂O): δ 58.91, 58.61 ppm; MS (negativemode): calcd. for C₁₄H₂₁N₅O₆PS, 418 (M); found m/z, 418.

[0085] Nucleoside 1d: ¹H NMR (D₂O): δ 7.71 (s, 1H), 6.28 (t, 1H, J=7.0Hz), 4.53-4.54 (m, 1H), 4.14-4.17 (t, 1H, J=2.5 Hz), 4.06-4.07 (m, 2H),3.83-3.88 (m, 2H), 2.30-2.33 (m, 2H), 1.90 (d, 3H, J=4.4 Hz), 1.50-1.56(m, 2H), 1.24-1.31 (m, 2H), 0.81 (t, 3H, J₁=7.4 Hz) ppm; ³¹P NMR (D₂O):δ 58.32, 58.24 ppm; MS (negative mode): calcd. for C₁₄H₂₂N₂O₇PS, 393(M); found m/z, 393.

[0086] Nucleoside 1e: ¹H NMR (D₂O): δ 8.44 (d, 1H, J=10 Hz), 8.23 (s,1H), 6.44-6.47 (m, 1H), 4.25 (s, 1H), 3.94-4.06 (m, 2H), 3.32-3.46 (m,2H), 2.83-2.89 (m, 1H), 2.57-2.62 (m, 1H), 1.84-1.90 (m, 1H), 1.40-1.44(m, 2H), 1.29-1.30 (m, 4H), 0.82-0.90 (m, 2H) ppm; ³¹P NMR (D₂O): δ58.73, 58.28 ppm.

[0087] Nucleoside 1f: ¹H NMR (D₂O): δ 8.7.94 (d, 1H, J=7.6 Hz), 6.23 (t,1H, J=6.7 Hz), 6.03 (d, 1H, J=7.8 Hz), 4.51 (d, 1H, J=2.9 Hz), 4.17 (s,1H), 4.03-4.08 (m, 2H), 3.67-3.70 (m, 2H), 2.38-2.42 (m, 1H), 2.20-2.25(m, 1H), 2.06-2.12 (m, 4H), 1.61 (br, 1H), 1.45, 1.46 (2xS, 4H)1.14-1.16 (m, 2H) ppm; ³¹P NMR (D₂O): δ□58.79, 58.70 ppm.

[0088] Nucleoside 1g: ¹H NMR (D₂O): δ 8.10 (d, 1H, J=7.3 Hz), 6.24-6.27(m, 1H), 4.19 (s, 1H), 3.97-4.04 (m, 2H), 3.38-3.52 (m, 2H), 2.79-2.86(m, 1H), 2.48-2.53 (m, 1H), 1.89-1.94 (m, 1H), 1.45-1.50 (m, 2H), 1.34(bs, 4H), 0.87-1.00 (m, 2H) ppm; ³¹P NMR (D₂O): δ 58.64, 58.23 ppm.

[0089] Nucleoside 1h: ¹H NMR (D₂O): δ 7.71 (s, 1H), 6.28 (t, 1H, J=7.0Hz), 4.55-4.56 (m, 1H), 4.15 (d, 1H, J=2.2 Hz), 4.04-4.10 (m, 2H),3.66-3.74 (m, 2H), 2.31-2.34 (m, 2H), 2.08-2.14 (m, 1H), 1.90 (d, 3H,J=5.5 Hz), 1.61-1.63 (m, 2H), 1.46-1.47 (m, 4H), 1.12-1.17 (m, 2H) ppm;³¹P NMR (D₂O): δ 58.76, 58.61 ppm.

[0090] Nucleoside 1k: ¹H NMR (D₂O): δ 8.06-8.08 (m, 1H), 6.24 (t, 1H,J=6.6 Hz), 6.11-6.13 (m, 1H), 5.26 (s, 1H), 4.50-4.53 (m, 1H), 4.18 (d,1H, J=2.0 Hz), 4.05-4.12 (m, 2H), 3.78-3.88 (m, 2H), 2.41-2.45 (m, 1H),2.22 -2.30 (m, 4H), 2.09-2.18 (m, 2H), 1.95-2.01 (m, 2H), 1.18 (s, 3H),1.00 (d, 1H, 3.9 Hz), 0.71 (d, 3H, 2.0 Hz) ppm; ³¹P NMR (D₂O): δ 58.91,58.67 ppm.

[0091] Nucleoside 1l: ¹H NMR (D₂O): δ 7.74 (d, 1H, J=6.7 Hz), 6.30 (t,1H, J=7.0 Hz), 5.23 (s, 1H), 4.54 (d, 1H, J=2.1 Hz), 4.14 (s, 1H),4.06-4.08 (m, 2H), 3.80-3.84 (m, 2H), 2.22-2.35 (m, 5H), 2.07 -2.17 (m,2H), 2.00 (s, 1H), 1.86-1.92 (m, 4H), 1.24 (d, 1H, J=6.8 Hz), 1.16 (s,3H), 1.09 (d, 1H, J=6.8 Hz), 0.97 (d, 1H, J=8.3 Hz), 0.69 (s, 3H) ppm;³¹P NMR (D₂O): δ 58.91, 58.67 ppm.

[0092] Nucleoside 1n: ¹H NMR (D₂O): δ 7.93 (d, 1H, J=7.6 Hz), 6.22 (t,1H, J=6.3 Hz), 6.01-6.03 (m, 1H), 5.70 (s, 1H), 4.48-4.50 (m, 1H), 4.22,4.23 (2xs, 2H), 4.16 (d, 1H, J=1.9 Hz), 4.05-4.10 (m, 2H), 2.37-2.42 (m,1H), 2.18-2.22 (m, 1H), 1.98 -2.06 (m, 4H), 1.81-1.87 (t, 1H, J=14.7Hz), 1.66 (s, 3H), 1.30-1.35 (m, 1H) ppm; ³¹P NMR (D₂O): δ 59.69, 59.15ppm.

[0093] Nucleoside 1p: ¹H NMR (D₂O): δ 7.71 (d, 1H, J=5.1 Hz), 6.27 (t,1H, J=6.9 Hz), 5.71 (s, 1H), 4.54 (t, 1H, J=2.5 Hz), 4.25 (m, 2H), 4.15(s, 1H), 4.08 (m, 2H), 2.29-2.33 (m, 2H), 2.00-2.07 (m, 4H), 1.86 -1.89(m, 4H), 1.71-1.76 (m, 1H), 1.68 (s, 3H), 1.31-1.38 (m, 1H) ppm; ³¹P NMR(D₂O): δ 59.09, 59.00 ppm.

[0094] Nucleoside 1r: ¹H NMR (D₂O): δ 7.95 (d, 1H, J=7.6 Hz), 6.20-6.24(q, 1H), 6.04-6.06 (dd, 1H, J=7.6 Hz), 5.96-5.99 (dd, 1H, J₁=12.9 Hz,J₂=3.5 Hz), 4.80-4.90 (dd, 1H), 4.48-4.50 (m, 1H), 4.32-4.46 (m, 2H),4.14-4.18 (m, 2H), 4.04-4.10 (m, 2H), 3.95-3.98 (m, 1H), 2.40-2.46 (m,1H), 2.17-2.25 (m, 1H), 1.89 (s, 4H), 1.45 (d, 3H, 9.2 Hz), 1.38 (d, 3H,4.8 Hz), 1.28 (d, 3H, 2.5 Hz), 1.24 (d, 3H, 9.2 Hz) ppm; ³¹P NMR (D₂O):δ 59.75, 59.24 ppm.

[0095] Nucleoside 1t: ¹H NMR (D₂O ): □δ 7.70 (s, 1H), 6.28, 6.23 (2xt,1H), 5.99, 5.96 (dd, 1H, J₁=7.6 Hz, J₂=2.6 Hz), 5.96-5.99 (dd, 1H,J₁=12.9 Hz, J₂=3.5 Hz), 4.80-4.90 (2xd, 1H), 4.90, 4.81 (2xd, 1H),4.52-4.54 (m, 1H), 4.33-4.47 (m, 2H), 4.04-4.17 (m, 4H), 3.96-3.99 (m,1H), 2.24-2.42 (m, 2H), 1.91 (d, 3H, J=2.3 Hz), 1.86 (s, 3H), 1.44 (2xs,3H, 9.2 Hz), 1.38 (2xs, 3H), 1.24-1.29 (m, 6H) ppm; ³¹P NMR (D₂O): δ59.75, 59.24 ppm.

[0096] Nucleoside 1v: ¹H NMR (D₂O): δ 7.95 (d, 1H, J=7.9 Hz), 6.25 (t,1H, J=6.8 Hz), 6.04 (d, 1H, J=7.5 Hz), 4.52-4.55 (m, 1H), 4.42 (t, 1H,J=9.9 Hz), 4.18 (d, 1H, J=2.1 Hz), 2.38-2.43 (m, 1H), 2.12 -2.28 (m,2H), 1.64-1.79 (m, 2H), 1.06-1.25 (m, 4H), 0.76-0.79 (m, 9H) ppm; ³¹PNMR (D₂O): δ 58.66, 58.61 ppm.

[0097] Nucleoside 1x: ¹H NMR (D₂O): δ 7.73 (d, 1H, J=5.6 Hz), 6.27 (t,1H, J=6.8 Hz), 4.54-4.57 (m, 1H), 4.43 (t, 1H, J=9.7 Hz), 4.14 (s, 1H),4.06-4.09 (m, 2H), 2.31 -2.36 (m, 2H), 2.13-2.20 (m, 1H), 1.91 (s, 3H),1.73-1.79 (m, 1H), 1.64-1.69 (m, 1H), 1.07-1.25 (m, 4H), 0.75-0.79 (m,9H) ppm; ³¹P NMR (D₂O): δ 58.52, 58.46 ppm.

EXAMPLE 3

[0098] Biological Testing of Inhibition of CMV

[0099] Selected compounds of the invention were tested against humancytomeglovirus (HCMV). Briefly, a 96 well cell-based assay was used withhuman foreskin infected with HCMV strain with an MOI of 0.05 plaqueforming units per ml. Each well was treated once with a 25 micromolardose of test compound. Five days following treatment with the testcompound, total cellular DNA was harvested after cell lysis. Celllysates were applied to a Nylon membrane on a dot blot apparatus, theblots hybridized with a probe specific for HCMV DNA, and the blotsscanned and analyzed using Scan analysis software. Tested compoundsshowed significant inhibition of viral growth relative to controlsamples.

EXAMPLE 4

[0100] Biological Testing of Inhibition of HSV-1

[0101] Selected compounds of the invention were tested against HerpesSimplex Virus Type 1 (HSV-1). Briefly, a 48 well cell-based assay wasused with vero cells infected with HSV-1 strain with an MOI of 0.005plaque forming units per ml. Each well was treated once with a 25micromolar dose of test compound at three hours post infection. Two daysfollowing treatment with the test compound, plaque reduction wasdetermined to determine cytotoxic compounds. Approximately 30% of thecompounds tested were non-cytotoxic in plaque reduction assays.

[0102] Cytotoxicity determinations of those compounds of the inventionwhich demonstrated cytotoxicity in plaque reduction assays were thenbased on a 96 well cell-based assay MTT assays (Sigma). Briefly, 24 hfollowing cells seeded on plates, dilutions of test compounds were addedand then incubated for two days in 5% CO2 at 37° C. The MTT assay wasthen carried out as directed by the manufacturer. Absorbance values werethen read at 570 and 600 nm using a multiscan plate reader.

EXAMPLE 5

[0103] Biological Testing of Inhibition of HBV

[0104] Selected compounds of the invention (W198-10, W198-21, W198-22,and W198-24) were tested against hepatits B virus (HBV):

[0105] Briefly, confluent 2.2.15 cell cultures infected with an HBVstrain were treated with 9 consecutive daily doses of fourconcentrations of test compound. Extracellular virion HBV DNA levelswere followed 24 hours after the last treatment. The level of HBV virionDNA in the 24 control (untreated) cultures in these experiments was114±16 pg/ml culture medium.

[0106] Cells for toxicity analyses were cultured and treated with fourconcentrations of the test compound. Uptake of neutral red dye was usedto determine the relative level of toxicity 24 hours following the lasttreatment. The absorbance of internalized dye at 510 nm (A₅₁₀) was usedfor the quantitative analysis. The percentage of dye uptake in thecontrol (untreated) cell cultures was 100±3.

[0107] Tested compounds showed significant inhibition of viral growthrelative to control samples, with no significant toxicity atconcentrations for antiviral activity used, as shown in Tables 3-5.TABLE 3 Selectivity Indexes of test compounds against HBV replication.Selectivity Index Compound CC₅₀ (μM) EC₅₀ (μM) EC₉₀ (μM) (CC₅₀/EC₉₀)W198-10 >300 7.7 ± 0.9 24 ± 0.8 13 W198-21 >300 5.3 ± 0.6 19 ± 2.1 16W198-22 >300  10 ± 1.1 32 ± 3.2 >9.4 W198-24 >300  12 ± 1.2 39 ± 4.1>7.7

[0108] TABLE 4 Toxicity analysis of test compounds in 2.2.15 cells.Neutral Red Dye Uptake at Indicated Drug Concentration (% of control)Compound 300 μM 100 μM 30 μM 10 μM W198-10  98 ± 1  99 ± 1 102 ± 2 100 ±1 W198-21 100 ± 2 100 ± 1  99 ± 1  99 ± 3 W198-22 103 ± 2 102 ± 2 101 ±3  99 ± 2 W198-24 102 ± 1 103 ± 1 102 ± 2 100 ± 1

[0109] TABLE 5 Antiviral analysis of test compounds in 2.2.15 cells. HBVVirion DNA Levels at indicated Drug Concentration (pg/ml culture)Compound 10 μM 1.0 μM 0.1 μM 0.01 μM W198-10 46 ± 2 139 ± 10 121 ± 10127 ± 10 W198-21 35 ± 4 117 ± 12 121 ± 13 137 ± 14 W198-22 59 ± 2 152 ±11 122 ± 13 129 ± 13 W198-24 62 ± 3 149 ± 25 133 ± 12 140 ± 15

[0110] The invention has been described in detail with reference topreferred embodiments thereof. However, it will be appreciated thatthose skilled in the art, upon consideration of this disclosure, maymake modifications and improvements within the spirit and scope of theinvention as set forth in the following claims.

What is claimed is:
 1. A compound library comprising two or morecompounds of the following

Formula I or I′: wherein L is a linking group such as e.g. an amide,ester, diester or the like, or an optionally substituted alkylene (e.g.C₁₋₂₀ alkylene), optionally substituted alkenylene (e.g., C₂₋₂₀alkenylene) or alkynylene (e.g., C₂₋₂₀ alkynylene) having such groupseither as a chain member of pendant to the chain, and which may beoptionally substituted with one or more substituents selected from agroup consisting of O, S, Se, NR¹NR², CR¹CR², OR, SR and SeR, or anenzymatically reactive; Q is carbon or a heteroatom such as O, S or N; Ris hydrogen or a hydroxyl group or an optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkenyl, optionally substituted carbocyclicaryl, an optionally substituted mononucleotide, an optionallysubstituted polynucleotide, or an optionally substituted heteroaromaticor heteroalicyclic group preferably having from 1 to 3 separate or fusedring and 1 to 3 N, O or S atoms; R¹, R², R³ and R⁴ are eachindependently selected from a group as defined by R; B is optionallysubstituted adenine, optionally substituted thymidine, optionallysubstituted cytosine or an optionally substituted guanine, preferablywhere the optional substituents are alkyl, carbocyclic aryl, orheteroaromatic or heteroalicyclic group preferably having from 1 to 3separate or fused rings and 1 to 3 N, O or S atoms, or a heterocyclicstructure that is covalently linked to the sugar ring; n=1 to 5; andpharmaceutically acceptable salts thereof.
 2. The library of claim 1wherein at least one compound has a sugar group is in open chain form.3. The library of claim 1 wherein an enantiomerically enriched mixtureof a compound is present.
 4. A compound library comprising two or morecompounds of the following Formula II or II′:

X and Y are each independently selected from a group consisting of O, S,Se, NR¹NR², CR¹CR², OR, SR and SeR, or one or both of X and Y are anenzymatically reactive moiety; R is optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkenyl, optionally substituted carbocyclicaryl, an optionally substituted mononucleotide, an optionallysubstituted polynucleotide, or an optionally substituted heteroaromaticor heteroalicyclic group preferably having from 1 to 3 separate or fusedring and 1 to 3 N, O or S atoms; R¹, R², and R³ are each independentlyselected from a group as defined by R; B is optionally substitutedadenine, optionally substituted thymidine, optionally substitutedcytosine or an optionally substituted guanine, preferably where theoptional substituents are alkyl, alkynyl, carbocyclic aryl, orheteroaromatic or heteroalicyclic group preferably having from 1 to 3separate or fused ring and 1 to 3 N, O or S atoms, or a heterocyclicstructure that is covalently linked to the sugar ring; andpharmaceutically acceptable salts thereof.
 5. The library of claim 1wherein at least one compound is of the following formula IIA or IIA′:

X and Y are each independently selected from a group consisting of O, S,Se, NR¹NR², CR¹CR², OR, SR and SeR, or one or both of X and Y are anenzymatically reactive moiety; R is optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkenyl, optionally substituted carbocyclicaryl, an optionally substituted mononucleotide, an optionallysubstituted polynucleotide, or an optionally substituted heteroaromaticor heteroalicyclic group preferably having from 1 to 3 separate or fusedring and 1 to 3 N, O or S atoms; R¹, R² and R³ are each independentlyselected from a group as defined by R; B is optionally substitutedadenine, optionally substituted thymidine, optionally substitutedcytosine or an optionally substituted guanine, preferably where theoptional substituents are alkyl, alkynyl, carbocyclic aryl, orheteroaromatic or heteroalicyclic group preferably having from 1 to 3separate or fused ring and 1 to 3 N, O or S atoms, or a heterocyclicstructure that is covalently linked to the sugar ring; andpharmaceutically acceptable salts thereof.
 6. The library of claim 1wherein the library has been constructed using solid-phase synthesis. 7.The library of claim 1 wherein the library has been constructed usingsolution phase synthesis.
 8. Use of the library of claim 1 to find aspecific interacting partner for a nucleic acid.
 9. Use of the libraryof claim 1 to find a specific interacting partner for a protein.
 10. Theuse of claim 8 wherein the nucleic acid is RNA or DNA.
 11. The use ofclaim 9 wherein the protein is an antibody, receptor or ligand.
 12. Acompound of the following Formula I or I′:

wherein L is a linking group such as an amide, ester, diester or thelike which may be optionally substituted with one or more substituentsselected from a group consisting of O, S, Se, NR¹NR², CR¹CR², OR, SR andSeR, or an enzymatically reactive moiety; Q is carbon or a heteroatomsuch as O, S or N; R is hydrogen or a hydroxyl group or an optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aralkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkenyl, optionallysubstituted carbocyclic aryl, an optionally substituted mononucleotide,an optionally substituted polynucleotide, or an optionally substitutedheteroaromatic or heteroalicyclic group preferably having from 1 to 3separate or fused ring and 1 to 3 N, O or S atoms; R¹, R², R³ and R⁴ areeach independently selected from a group as defined by R; B isoptionally substituted adenine, optionally substituted thymidine,optionally substituted cytosine or an optionally substituted guanine,preferably where the optional substituents are alkyl, carbocyclic aryl,or heteroaromatic or heteroalicyclic group preferably having from 1 to 3separate or fused rings and 1 to 3 N, O or S atoms, or or B isheteroaromatic or heteroalicyclic group other than an adenine,thymidine, cytosine or guanine; N is an integer of from 1 (where to forma 5-membered ring as depicted or 5-membered acyclic group) to 5; andpharmaceutically acceptable salts thereof.
 13. A compound of thefollowing Formula II or II′:

X and Y are each independently selected from a group consisting of O, S,Se, NR¹NR², CR¹CR², OR, SR and SeR, or one or both of X and Y are anenymatically reactive moiety; R is optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkenyl, optionally substituted carbocyclicaryl, an optionally substituted mononucleotide, an optionallysubstituted polynucleotide, or an optionally substituted heteroaromaticor heteroalicyclic group preferably having from 1 to 3 separate or fusedring and 1 to 3 N, O or S atoms; R¹, R² and R³ are each independentlyselected from a group as defined by R; B is optionally substitutedadenine, optionally substituted thymidine, optionally substitutedcytosine or an optionally substituted guanine, preferably where theoptional substituents are alkyl, carbocyclic aryl, or heteroaromatic orheteroalicyclic group preferably having from 1 to 3 separate or fusedring and 1 to 3 N, O or S atoms, or a heterocyclic structure that iscovalently linked to the sugar ring; and pharmaceutically acceptablesalts thereof.
 14. A compound of claim 12 wherein the sugar group is inopen chain form.
 15. A compound of claim 12 wherein an enantiomericallyenriched mixture of a compound is present.
 16. A compound of thefollowing Formula IIA or IIA′:

X and Y are each independently selected from a group consisting of O, S,Se, NR¹NR², CR¹CR², OR, SR and SeR, or one or both of X and Y are anenzymatically reactive moiety; R is optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted arakyl, optionally substituted cycloalkyl,optionally substituted cycloalkenyl, optionally substituted carbocyclicaryl, an optionally substituted mononucleotide, an optionallysubstituted polynucleotide, or an optionally substituted heteroaromaticor heteroalicyclic group preferably having from 1 to 3 separate or fusedring and 1 to 3 N, O or S atoms; R¹, R² and R³ are each independentlyselected from a group as defined by R; B is optionally substitutedadenine, optionally substituted thymidine, optionally substitutedcytosine or an optionally substituted guanine, preferably where theoptional substituents are alkyl, carbocyclic aryl, or heteroaromatic orheteroalicyclic group preferably having from 1 to 3 separate or fusedring and 1 to 3 N, O or S atoms, or a heterocyclic structure that iscovalently linked to the sugar ring; and pharmaceutically acceptablesalts thereof.
 17. A method for treating virally infected cellscomprising administering to the cells an anti-viral effective amount ofa compound of claim
 12. 18. The method of claim 17 wherein the cells areinfected with a herpes virus.
 19. The method of claim 17 wherein thecells are infected with a cytomegalovirus.
 20. The method of claim 17wherein the cells are infected with a hepatitis B virus.
 21. A methodfor treating bacterially infected cells comprising administering to thecells an anti-bacterial effective amount of a compound of claim
 12. 22.The method of claim 21 wherein the mammal is suffering from amycobacterium infection.
 23. A method for treating a mammal sufferingfrom or susceptible to a viral infection, comprising administering tothe mammal an anti-viral effective amount of a compound of claim
 12. 24.The method of claim 23 wherein the mammal is suffering from a herpesinfection.
 25. The method of claim 23 wherein the mammal is sufferingfrom a cytomegalovirus infection.
 26. The method of claim 23 wherein themammal is suffering from a hepatitis B virus infection.
 27. A method fortreating a mammal suffering from or susceptible to a bacterialinfection, comprising administering to the mammal an anti-bacterialeffective amount of a compound of claim
 12. 28. A pharmaceuticalcomposition comprising a compound of any one of claim 12 and apharmaceutically acceptable carrier.
 29. A method for synthesis of acompound library, comprising: adding one or more reagents to a reactionvessel capable of agitation and containing a resin reaction supportmaterial; agitating the reaction vessel during reaction of the reagents;and centrifuging the reaction vessel and removing desired reactionmaterials therefrom.
 30. The library of claim 1 wherein the librarycomprises phosphorothioate compounds.
 31. The library of claim 1 whereinthe library comprises thiophosphoramidate compounds.
 32. The library ofclaim 1 wherein the library comprises phosphoramidothionate compounds.33. The library of claim 1 wherein the library comprises carbamatecompounds.
 34. The compound of claim 12 wherein the compound is aphosphorothioate compound.
 35. The compound of claim 12 wherein thecompound is a thiophosphoramidate compound.
 36. The compound of claim 12wherein the compound is a phosphoramidothionate compound.
 37. Thecompound of claim 12 wherein the compound is a carbamate compound.